1,3-Diaryl-2-imino-imidazolidines and compositions thereof

ABSTRACT

The invention relates to new compounds of the general formula (I), ##STR1## wherein R 1  and R 5  each represent a phenyl group, optionally substituted, 
     R 2  stands for hydrogen, formyl group, carboxy group, lower alkoxycarbonyl group, hydroxy-(lower)-alkoxycarbonyl group, or a lower alkyl group, optionally substituted, 
     R 3  and R 4  each represent hydrogen atom or a lower alkyl group, with the proviso that when R 1  and R 5  each represent a phenyl group, R 2  and R 3  may not stand for hydrogen. 
     These compounds possess valuable biological properties, and can be applied primarily as antiphlogistic or diuretic agents.

The invention relates to new substituted1,3-diaryl-2-imino-imidazolidines and pharmaceutical compositionscontaining the same, as well as to a process for the preparationthereof.

The new compounds according to the invention correspond to the generalformula (I), ##STR2## wherein R¹ and R⁵ each represent a phenyl groupoptionally substituted with 1 to 3 lower alkoxy, halo, lower alkyl,monohalo-(lower-alkyl, dihalo-(lower)-alkyl and/or trihalo-(lower)-alkylgroups,

R² stands for hydrogen, formyl group, carboxy group, loweralkoxycarbonyl group, hydroxy-(lower)-alkoxycarbonyl group, or a loweralkyl group optionally substituted with a hydroxy group, 1 to 3 halogenatoms, a lower alkoxy group, a lower alkanoyloxy group, a loweralkylsulfonyloxy group, an arylsulfonyloxy group, a free or etherifiedmercapto group, a cyano group, a nitro group, an unsubstituted orsubstituted amino group or a group of the general formula --CO--Y,wherein

the etherified mercapto group is a group derived from a loweralkylmercaptan having optionally a mono- or di-(lower alkyl)-aminosubstituent, a mercapto-(lower)-alkanecarboxylic acid having optionallyan amino substituent or a 3 to 7-membered heterocyclic compoundcontaining 1 to 4 nitrogen, sulfur and/or oxygen atoms in the ring andhaving a mercapto substituent,

the substituted amino group is a group having one or two identical ordifferent lower alkyl substituents or a C₂₋₆ α, ω-alkylene substituentcontaining optionally a further hetero atom, such as nitrogen, sulfur oroxygen atom, in the carbon chain, and

Y stands for hydroxy, amino, lower alkoxy or hydroxy-(lower)-alkoxygroup,

R³ and R⁴ each represent hydrogen atom or a lower alkyl group,

R⁶ stands for hydrogen atom, with the proviso that when R¹ and R⁵ L eachrepresent a phenyl group and n is equal to zero, R² and R³ may not standfor hydrogen.

The compounds of the general formula (I) may appear in the form ofvarious isomers and isomeric mixtures. All of the possible isomers andmixtures thereof are embraced by the scope of the invention.

The scope of the invention also embraces the pharmaceutically acceptableacid addition salts of the compounds having the general formula (I),furthermore their complexes formed with inorganic salts.

The lower alkyl and lower alkoxy groups mentioned above are thosecontaining 1 to 5 carbon atoms, whereas the lower acyloxy groups maycontain 2 to 5 carbon atoms. All of these carbon chains may be straightor branched. The term "halo" includes iodine, bromine, chlorine andfluorine atoms.

Based on the above, in the compounds of the general formula (I)

R¹ and R⁵ each may stand for e.g. phenyl, 2,6-dimethylphenyl,2,3-dimethylphenyl, 2,4,6-trimethylphenyl, 2-chloro-6-methylphenyl,3-trifluoromethylphenyl, 4-chlorophenyl, 4-methoxyphenyl,2,6-diethylphenyl or 2,6-dichlorophenyl group,

R² may represent e.g. hydrogen atom or a methyl, n-butyl, hydroxymethyl,mercaptomethyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl,trifluoromethyl, trichloromethyl, methoxymethyl, methylmercaptomethyl,carboxymethyl-mercapto-methyl, (β-diethylaminoethyl)-mercapto-methyl,2-thienyl-mercaptomethyl, aminomethyl, 2-aminoethyl,diethylaminomethyl-morpholinomethyl, cyanomethyl, carboxamidomethyl,carboxymethyl, ethoxycarbonylmethyl, (β-hydroxy-ethoxy)-carbonylmethyl,nitromethyl, carboxy, methoxycarbonyl, (β-hydroxyethoxy)-carbonyl orformyl group,

R³ and R⁴ each may stand for e.g. hydrogen or a methyl group, and

R⁶ may represent e.g. hydrogen atom.

Only one compound is described in the literature which is structurallyrelated to the new compounds of the general formula (I). This compoundis 1,3-diphenyl-2-imino-imidazolidine, which is prepared by reactingphenylcyanamide with 1,2-dibromoethane and subjecting the resultingethylene-bis-phenyl-cyanamide to partial hydrolysis and spontaneouscyclization (see Traube and Wedekind: Ber. 33, 1385/1900/), or bysubjecting the respective2,2'-bis(1",3"-diphenyl)-imidazolidinium-halides to alkaline splitting(see Wanzlick et al.: Ber. 98, 3170/1965/).

No biological activity is assigned to this compound.

Now it has been found that the new compounds of the general formula (I),furthermore their pharmaceutically acceptable acid addition salts andcomplexes formed with inorganic salts exert valuable antiphlogisticeffects.

The new compounds of the invention can be prepared as follows:

(a) a compound of the general formula (II), ##STR3## wherein R¹, R², R³,R⁴, R⁵ and n are as defined above, is reacted with a cyanogen halide toobtain a compound of the general formula (I), wherein R¹, R², R³, R⁴, R⁵are as defined above and R⁶ is hydrogen, in the form of its hydrohalide,or

(b) a compound of the general formula (III), ##STR4## wherein R¹, R²,R³, R⁴, R⁵ are as defined above and R⁶ stands for hydrogen or a loweralkyl group, is subjected to ring closure by desulfuration with a heavymetal oxide, or

(c) a compound of the general formula (IV), ##STR5## wherein R¹, R², R³,R⁴, R⁵ are as defined above, is subjected to partial hydrolysis coupledwith spontaneous ring closure to form a compound of the general formula(I), wherein R⁶ stands for hydrogen and R¹, R², R³, R⁴, R⁵ have the samemeanings as defined above, with the proviso that R¹ and R⁵ are alwaysthe same, or

(d) a compound of the general formula (V), ##STR6## wherein R¹, R², R³,R⁴ are as defined above and X is halo, is reacted with a cyanamide ofthe general formula R⁵ --NH--CN, wherein R⁵ is as defined above, and, ifdesired, a compound of the general formula (I) is converted into anothercompound of the general formula (I) by methods known per se, and/or, ifdesired, a free base of the general formula (I) is liberated from itssalt, and/or, if desired, a free base of the general formula (I) isconverted into its acid addition salt or complex formed with aninorganic salt, and/or, if desired, the individual isomers of theproduct are separated from each other.

According to a particularly preferred variant of method (a) a compoundof the general formula (II), wherein R¹, R², R³, R⁴, R⁵ are as definedabove, is reacted with 1.0 to 3.0 moles of a cyano halide, calculatedfor 1 mole of the starting substance, in an appropriate solvent, such asethanol, n-propanol, isopropanol, n-butanol, benzene, toluene, xylene orchlorobenzene, at a temperature between room temperature and the boilingpoint of the reaction mixture, preferably at about 80° C. to 130° C.

The starting substances of the general formula (II) are in part knownfrom the literature (see e.g. L. Shapiro et al.: J. Am. Chem. Soc. 80,3734/1958/; U.S. patent specification No. 2,993,831; I. K. Lewis et al.:J. Org. Chem. 29, 1183/1964/; A. E. Schouten: Rec. trav. chim. 56,541/1937/; R. Daniels and B. D. Martin: J. Org. Chem. 27, 178/1962/; A.F. McKay and E. J. Tarlton: J. Am. Chem. Soc. 74, 2978/1959/), or can beprepared according to methods known per se.

Method (b) of the process of the invention is performed preferably sothat a compound of the general formula (III), wherein R¹, R², R³, R⁴, R⁵are as defined above and R⁶ stands for hydrogen or a lower alkyl group,is reacted with a heavy metal oxide, such as mercury(II)oxide orlead(II)oxide, in an inert solvent, such as toluene, xylene orchlorobenzene, at a temperature of about 80° C. to 140° C.

The starting substances of the general formula (III) can be prepared bymethods known per se (see e.g. published German patent application No.2,140,405; D. T. Elmore and J. R. Ogle: J. Chem. Soc. 1958, 1141).

According to a preferred variant of method (c) of the invention thecompounds of the general formula (IV), wherein R¹, R², R³, R⁴, R⁵ are asdefined above and R¹ and R⁵ are always the same, are subjected topartial hydrolysis under the conditions applied by Traube and Wedekind(loc. cit.), whereupon a spontaneous cyclization also takes place. Inthis way compounds of the general formula (I), wherein R¹, R², R³, R⁴,R⁵ are as defined above, R¹ and R⁵ are always the same and R⁶ stands forhydrogen, are obtained.

The starting substances of the general formula (IV) are prepared bymethods known per se (see Traube and Wedekind, loc. cit.).

Method (d) of the invention is performed preferably so that a compoundof the general formula (V), wherein R¹, R², R³, R⁴, and X are as definedabove, is reacted with a cyanamide of the general formula R⁵ --NH--CN,wherein R⁵ is as defined above, at a temperature between about roomtemperature and 100° C., either in a solvent-free medium or in thepresence of a solvent, such as benzene, toluene, xylene,dimethylformamide or dimethylsulfoxide, in the optional presence of abase, such as sodium methoxide, sodium ethoxide or potassiumtert.-butoxide. This method yields compounds of the general formula (I),wherein R¹, R², R³, R⁴, R⁵ are as defined above and R⁶ stands forhydrogen.

Those compounds of the general formula (I), wherein R¹, R³, R⁴, R⁵, R⁶are as defined above and R² stands for formyl group, can be prepared byoxidizing a compound of the general formula (I), wherein R² ishydroxymethyl, R¹, R³, R⁴, R⁵ are as defined above and R⁶ stands for agroup of the general formula R⁷ --CO-- wherein R⁷ stands for hydrogen, alower alkyl group having optionally 1 to 3 halogen substituents, a loweralkoxy group, an aryloxy group, an aralkoxy group, a phenyl group havingoptionally a halogen or lower alkyl substituent, or a mono- orpolycyclic cycloalkyl group of up to 10 carbon atoms, with anappropriate oxidizing agent, such as manganese dioxide or bariummanganate, at a temperature between about room temperature and 100° C.and in a solvent medium, such as benzene, toluene, xylene, chloroform,1,2-dichloroethane or acetonitrile, and, if necessary, splitting off theR⁷ --CO-- group of the resulting product by treating it with an acid,such as a mineral acid (e.g. hydrochloric acid or sulfuric acid) or anorganic acid (e.g. citric acid, fumaric acid or maleic acid) in water ora lower aliphatic alcohol or in a mixture of these solvents at atemperature between about room temperature and 120° C.

If a compound of the general formula (I), wherein R¹, R³, R⁴, R⁵, R⁶ areas defined above and R² stands for carboxy group, is to be prepared, acompound of the general formula (I), wherein R² is hydroxymethyl, R⁶ isa group of the general formula R⁷ --CO-- and R¹, R³, R⁴, R⁵, R⁷ are asdefined above, is oxidized, preferably with potassium permanganate, inan appropriate solvent, such as dioxane, tetrahydrofuran,diethyleneglycol dimethyl ether, water or a mixture thereof, in thepresence of a base, such as sodium or potassium hydroxide, at atemperature between 0° C. and 50° C. If necessary, the R⁷ --CO-- groupof the resulting substance can be split off as described in the previousparagraph. If desired, the resulting acids can be converted into theiresters by reacting them with an excess of a lower aliphatic mono- orpolyol at a temperature between about 0° C. and 100° C. in the presenceof an acid, preferably dry hydrochloric acid.

Those compounds of the general formula (I), wherein R¹, R³, R⁴, R⁵, R⁶are as defined above and R² stands for a lower alkyl group having alower alkoxy substituent, can be prepared by reacting a compound of thegeneral formula (I), wherein R² is hydroxy-(lower)-alkyl group, R⁶ is agroup of the general formula R⁷ --CO--, and R¹, R³, R⁴, R⁵, R⁷ are asdefined above, with a lower alkyl halide in an appropriate solvent, suchas acetone, methyl-ethyl-ketone, dimethylformamide or dimethylsulfoxide,in the presence of an inorganic base, such as sodium hydride, potassiumtert.-butoxide or silver oxide. If desired, the R⁷ --CO-- group of theresulting compound can be split off as described above.

If a compound of the general formula (I), wherein R² is a lower alkylgroup having a lower acyloxy substituent, R⁶ is a group of the generalformula R⁷ --CO--, and R¹, R³, R⁴, R⁵, R⁷ are as defined above, is to beprepared, a compound of the general formula (I), wherein R² ishydroxy-(lower)-alkyl, R⁶ stands for hydrogen, and R¹, R³, R⁴, R⁵ are asdefined above, is reacted with an excess of a lower alkanecarboxylicanhydride at a temperature of 100° C. to 150° C. In the resultingcompound the acyl group contained in R² is the same as that representedby R⁶. If desired, the resulting compound can be treated with potassiumor sodium hydrixide at room temperature in a solvent, such as methanol,ethanol, water or mixtures thereof, whereupon the acyl substituent of R²is split off selectively, and a compound of the general formula (I),wherein R² is hydroxy-(lower)-alkyl, R⁶ is a group of the generalformula R⁷ --CO--, and R¹, R³, R⁴, R⁵, R⁷ are as defined above, isobtained.

Those compounds of the general formula (I), wherein R² is a lower alkylgroup having a lower acyloxy substituent, R⁶ is hydrogen and R¹, R³, R⁴,R⁵ and n are as defined above, can be prepared by reacting thehydrohalide of a compound of the general formula (I), wherein R² ishydroxy-(lower)-alkyl, R⁶ is hydrogen, and R¹, R³, R⁴, R⁵ are as definedabove, with the respective acyl chloride in an appropriate solvent, suchas dimethylformamide, dimethylsulfoxide or hexamethylphosphorictriamide, at a temperature of -20° C. to +50° C.

If a compound of the general formula (I), wherein R² ishalo-(lower)-alkyl, is to be prepared, a compound of the general formula(I), wherein R² is hydroxy-(lower)-alkyl, R⁶ is a group of the generalformula R⁷ --CO--, and R¹, R³, R⁴, R⁵, R⁷ are as defined above, isreacted with an appropriate halogenating agent, such as thionylchloride, phosphorus pentachloride, chloromethylene-dimethyl-ammoniumchloride, bromomethylene-dimethyl-ammonium bromide, triphenylphosphinedibromide or triphenylphosphine diiodide, in a solvent, such as benzene,toluene, xylene, chloroform, 1,2-dichloroethane, acetonitrile ordimethylformamide, at a temperature between room temperature and theboiling point of the reaction mixture. The reaction can be performedoptionally in the presence of a catalyst, such as dimethylformamide. Ifdesired, the R⁷ --CO-- group of the resulting compound is split off asdescribed above.

Those compounds of the general formula (I), wherein R² is ahalo-(lower)-alkyl group, preferably a chloro-(lower)-alkyl group, R⁶ isa group of the general formula R⁷ --CO--, and R¹, R³, R⁴, R⁵, R⁷ are asdefined above, can be reacted with an alkali halide, such as sodium orpotassium bromide or iodide, in an appropriate solvent, such as a loweraliphatic alcohol (e.g. methanol, ethanol or isopropanol),dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide,at a temperature of about 0° C. to 150° C. In this reaction the halogenatom present in substituent R² is replaced by an other halogen atom,such as a chlorine atom is replaced by a bromine or iodine atom. Ifdesired, the R⁷ --CO-- group of the resulting compound can be split offas described above.

Those compounds of the general formula (I), wherein R² is a lower alkylgroup having a free or etherified mercapto substituent, are prepared byreacting a compound of the general formula (I), wherein R² ishalo-(lower)-alkyl, R¹, R³, R⁴, R⁵ are as defined above, and R⁶represents preferably a group of the general formula R⁷ --CO--, whereinR⁷ is defined as above, with an alkali thiobenzoate, such as sodium orpotassium thiobenzoate, in a solvent, such as acetone ormethyl-ethyl-ketone, at a temperature between about room temperature and80° C. The benzoyl group of the resulting S-benzoyl derivative is splitoff by treatment with a base, such as sodium methoxide or sodiumethoxide, in a lower aliphatic alcohol as solvent to obtain therespective mercapto compounds. If desired, the R⁷ --CO-- group of theresulting compounds is split off as described above, and/or, if desired,the mercapto group is etherified in a manner known per se.

Those compounds of the general formula (I), wherein R² is a lower alkylgroup having an etherified mercapto substituent, can also be prepared byreacting a reactive ester of a compound of the general formula (I),wherein R² is hydroxy-(lower)-alkyl, with a metal salt of the respectivemercaptane.

The compounds of the general formula (I), wherein R² is ahalo-(lower)-alkyl group, R⁶ is a group of the general formula R⁷--CO--, and R¹, R³, R⁴, R⁵, R⁷ are as defined above, can be reacted withan alkali metal nitrite, such as sodium or potassium nitrite, or with anoble metal nitrite, such as silver nitrite, in an appropriate solvent,such as diethyl ether, dimethylformamide, diethyleneglycol dimethylether, dimethylsulfoxide, sulfolane or hexamethylphosphoric triamide, ata temperature between about room temperature and 150° C., to obtain therespective compounds of the general formula (I), wherein R² is anitro-(lower)-alkyl group. If desired, the R⁷ --CO-- group of theresulting compounds can be split off as described above.

The compounds of the general formula (I), wherein R² is ahalo-(lower)-alkyl group, R⁶ stands for a group of the general formulaR⁷ --CO--, and R¹, R³, R⁴, R⁵, R⁷ are as defined above, can also bereacted with an alkali cyanide, preferably sodium cyanide, to form therespective compounds of the general formula (I), wherein R² iscyano-(lower)-alkyl. The reaction is performed in an appropriatesolvent, such as dimethylformamide, dimethylsulfoxide orhexamethylphosphoric triamide, at a temperature of about 80° C. to 150°C. The cyanide reactant is applied preferably in a 5 to 10-fold molarexcess. If desired, the resulting cyano compound is stirred in anaqueous alkaline medium at room temperature to obtain the correspondingderivative wherein R⁶ is hydrogen and R² is a carboxamido-(lower)-alkylgroup. These latter compounds can be treated, if desired, with a mineralacid, such as hydrochloric acid or sulfuric acid, in an appropriatesolvent, such as ethanol, isopropanol, butanol, water or mixturesthereof, at a temperature between room temperature and the boiling pointof the reaction mixture, to obtain compounds of the general formula (I),wherein R² is a carboxy-(lower)-alkyl group and R⁶ stands for hydrogen.If desired, these latter compounds can be converted into the respectiveesters by reacting them with an excess of a lower aliphatic mono- ordiol at a temperature of about 0° C. to 100° C. in the presence of ananhydrous mineral acid, such as dry hydrochloric acid. The excess of thealcohol also serves as solvent for the starting substance.

Those compounds of the general formula (I), wherein R² is a lower alkylgroup having a primary, secondary or tertiary amino substituent, can beprepared by reacting a compound of the general formula (I), wherein R²is a halo-(lower)-alkyl group, R⁶ stands for a group of the generalformula R⁷ --CO--, and R¹, R³, R⁴, R⁵, R⁷ are as defined above, with dryammonia, a primary or secondary lower aliphatic amine or a cyclic aminecontaining 2 to 6 ring carbon atoms and optionally a further heteroatom, such as nitrogen, sulfur or oxygen atom. The reaction can beperformed in the absence of a solvent or in a solvent medium, such as inacetone, acetonitrile, dimethylformamide, dimethylsulfoxide,hexamethylphosphoric triamide or sulfolane, at a temperature of about 0°C. to 150° C. If desired, the R⁷ --CO-- group of the resulting compoundcan be split off as described above.

The compounds of the general formula (I), wherein R² represents a loweralkyl group having a primary amino substituent, can also be prepared byreducing a compound of the general formula (I), wherein R² iscarboxamido-(lower)-alkyl, and R¹, R³, R⁴, R⁵, R⁶ are as defined above,with the hydride of a metal or a non-metallic element, a complex metalhydride, or--preferably--borane. The reaction can be performed e.g. indiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane ordiethyleneglycol dimethyl ether.

In order to liberate a base of the general formula (I) from its salt thesalt is dissolved in water, methanol, ethanol, dimethylformamide ormixtures thereof, then as aqueous solution of sodium or potassiumhydroxide or a methanolic sodium methoxide solution is added, and thebase is separated either by filtration or by extracting the mixture withan appropriate organic solvent, such as chloroform.

The acid addition salts of the compounds having the general formula (I)are prepared preferably so that the free base is dissolved in anappropriate solvent, such as methanol, ethanol, isopropanol oracetonitrile, then a solution of the acid in an appropriate solvent,preferably ethanol or isopropanol, is added, and the resulting salt isseparated from the reaction mixture optionally after evaporating a partor the total amount of the solvent(s) present.

Some representatives of these acid addition salts can also be preparedby adding the free base to a hot (60° to 100° C.) aqueous and/or loweralcoholic solution of the respective acid, cooling the mixture, andseparating the resulting crystalline salt.

In order to prepare the complexes of the compounds having the generalformula (I) the free base of the general formula (I) and the inorganicsalt are dissolved separately in an appropriate solvent, such asacetonitrile, ethyl acetate or a lower alkanol, admixing the solutionsat a temperature between about room temperature and 100° C., and thecrystalline complex salt separating upon cooling is filtered off.

Those compounds of the general formula (I), wherein one of R² and R³ ishydrogen and the other is different from hydrogen, contain a centre ofasymmetry (the carbon atom in position 4), thus they exist in the formof two optically active isomers. In order to separate the opticallyactive isomers from each other the racemic compound is treated with 0.5to 1.0 mole, calculated for 1 mole of the racemate, of an appropriateoptically active acid, such as d-tartaric acid orO,O-dibenzoyl-d-tartaric acid in a solvent medium, such as methanol,ethanol or ethyl acetate. Depending on the acid applied, the separatedsalt is an essentially optically pure isomer or it is to be purified byrepeated recrystallization steps to yield one of the isomers in purestate. The other isomer can be separated either as the free base or inthe form of its salt by processing the mother liquors. The salts can beconverted into the respective optically active bases by the methoddiscussed above.

As mentioned above, the compounds of the invention possess valuableantiphlogistic effects. Thus e.g. the ED₅₀ value of1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidine fumarate,determined on rats after oral administration in the carrageenin-inducedplantar oedema test (see Lence et al.: Arch. Int. Pharmacodyn. 136,237/1962/; C. A. Winter: Proc. Soc. Exp. Biol. Med. 11, 544/1962/), is11 mg/kg, whereas Indomethacine, applied as reference substance, has anED₅₀ value of 20 mg/kg in the same test. The above compound of theinvention exhibits a considerable activity in the cotton granuloma test(C. A. Winter: J. Pharm. Exp. Ther. 141, 369/1963/) and in the adjuvantarthritis test (B. B. Newbould: Brit. J. Pharmacol. Chemother. 21,137/1963/) as well.

1,3-Bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazoline fumarate isfar more advantageous than Indomethacine also with regard to itstoxicological properties. The LD₅₀ value of this compound, determined onrats after oral administration, amounts to 150 mg/kg, whereas that ofIndomethacine is only 20 mg/kg. Furthermore, the ulcerogeneous sideeffect of the new compound is far lower than that of Indomethacine, andthe new compound decreases gastric acid secretion to a moderate degree.based on the above, the new compound according to the invention can beapplied in the treatment of inflammatory disorders with a far greaterdegree of safety than Indomethacine. An interesting property of theabove new compound is that its mode of action differs from that of thecarboxylic acid type non-steroidal antiphlogistics; i.e. the newcompound does not inhibit the function of prostaglandine synthetaseenzyme, and its antiphlogistic effect is not connected with the blockingof serotonine or histamine receptors.

The following compounds of the invention also exert significantantiphlogistic effects:

1,3-bis(2',6'-dimethylphenyl)-2-imino-4-chloromethyl-imidazolidine,

1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-carboxylic acid,

1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-acetamide,

1,3-bis(4'-chlorophenyl)-2-imino-4-methyl-imidazolidine, and

1-(4'-chlorophenyl)-2-imino-3-(2',6'-dimethylphenyl)-4-methylimidazolidine.

Some of the compounds according to the invention, such as1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidine, alsoincrease the spontaneous activity of isolated rat uterine horn (Gaddum:Brit. J. Pharm. 1954, 240) and of the longitudinal smooth muscle ofguinea pig ileum (Paton and Vizi: J. Pharm. 1969, 10) when tested underin vitro conditions.

The compounds according to the invention can be applied in the therapyto treat inflammatory diseases. For these purposes the compounds can beadministered in the form of enterally, parenterally or locallyapplicable pharmaceutical compositions. Of the pharmaceuticalcompositions the orally applicable ones (such as tablets, coated tabletsand capsules) and the locally applicable ones (such as ointments) arethe most preferred.

The pharmaceutical compositions may contain the compounds according tothe invention either as the sole active ingredient or in combinationwith other substances of similar biological effects. The pharmaceuticalcompositions are prepared according to methods known per se, utilizingconventional pharmaceutical carriers, additives and/or auxiliary agents.Tablets for oral administration may contain, beside the activeingredient(s), e.g. carriers, such as glucose, lactose or mannitol,binding agents, such as gum arabic, gelatine, methyl cellulose,hydroxyethyl cellulose, pectin or polyvinyl pyrrolidine, disintegrationaids, such as starch, ultraamylopectin, alginic acid or colloidalsilica, furthermore glidants and lubricants, such as talc, magnesiumstearate or polyoxyethylene.

The daily dosage of the compounds according to the invention variesgenerally between about 0.1 mg/kg and 20 mg/kg, preferably between about1 mg/kg and 10 mg/kg. Of course, the actual dosage applied depends onother factors, such as the age, body weight and general condition of thepatient to be treated, as well.

The invention is elucidated in detail by the aid of the followingnon-limiting Examples.

EXAMPLE 1 1,3-Bis(2',6'-dimethylphenyl)-2-imino-imidazolidine Method (a)

500 ml of xylene are introduced into 1 liter four-necked flask equippedwith a stirrer, reflux condenser, thermometer and dropping funnel of 100ml capacity. 72.5 g (0.27 moles) of1,2-bis(2',6'-dimethylphenyl-amino)-ethane are dissolved in the xylene,and a solution of 33.9 g (0.32 moles) of cyanogen bromide in 200 ml ofxylene is added dropwise, within about 1.5 hours, to the stirredsolution at an internal temperature of 110° to 115° C. After theaddition the mixture is stirred for a further hour at 110° to 115° C.and then it is allowed to cool. The separated precipitate is filteredoff, washed with xylene and diethyl ether, and dried at roomtemperature. 100.5 g (99.4%) of1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine hydrobromide areobtained as colourless crystals melting at 289°-290° C.

The free base is liberated from its salt as follows: The above salt isdissolved in about 1 liter of water, the solution is filtered, and thefiltrate is rendered strongly alkaline by introducing 10 n aqueoussodium hydroxide solution. The separated colourless precipitate isfiltered off, washed thoroughly with water, and dried at 40° to 50° C.71.0 g (89.6%) of 1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidineare obtained; m.p.: 188°-190° C.

1,2-Bis(2',6'-dimethylphenyl-amino)-ethane, utilized as startingsubstance, can be prepared e.g. as described by Shapiro et al. (loc.cit.).

Method (b)

One proceeds as described in Method (a) above with the only differencethat chlorobenzene is applied as solvent instead of xylene.1,3-Bis(2',6'-dimethylphenyl)-2-imino-imidazolidine hydrobromide isobtained with a yield of 85.7%.

Method (c)

300 ml of xylene are introduced into a 500 ml four-necked flask equippedwith a stirrer, reflux condenser, thermometer and dropping funnel of 250ml capacity. 31.8 g (0.3 moles) of cyanogen bromide are dissolved in thexylene, and a solution of 26.85 g (0.1 moles) of1,2-bis(2',6'-dimethylphenylamino)-ethane in 150 ml of xylene is addeddropwise, within about 1 hour, to the stirred solution at 50° to 55° C.The resulting mixture is stirred for an additional hour at 50° to 55° C.and then it is cooled. The separated precipitate is filtered off, washedwith xylene and diethyl ether and dried at room temperature. Theresulting 32.5 g of light beige1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine hydrobromide aredissolved in about 700 ml of ethanol under boiling, the solution isdecolourized with carbon, filtered, and about 700 ml of dry diethylether are added to the filtrate in order to precipitate the product.30.5 g (81.5%) of the purified salt are obtained; m.p.: 292°-294° C.

Method (d)

0.5 g of yellow mercury(II)oxide are added to a solution of 0.5 g (1.53mmoles) of1-(2',6'-dimethylphenyl)-1-(β-/2',6'-dimethylphenyl-amino/-ethyl)-thioureain 30 ml of xylene, and the mixture is boiled for 4 hours. The mixtureis allowed to cool, the inorganic substances are separated byfiltration, and the solvent is removed from the filtrate under reducedpressure. The residual thick, yellow oil, weighing 0.5 g, is dissolvedin 5 ml of 1 n aqueous hydrochloric acid, the insolubles are filteredoff, and the filtrate is rendered alkaline with 2 n aqueous sodiumhydroxide solution. The separated precipitate is filtered off, washedwith water, and dried. 0.32 g (71.3%) of1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine are obtained; m.p.:187°-189° C.

1-(2',6'-dimethylphenyl)-1-(β-/2',6'-dimethylphenylamino/-ethyl)-thiourea,applied as starting substance in the above process, can be prepared asfollows:

(a) A solution of 5.35 g (20 mmoles) of1,2-bis(2',6'-dimethylphenyl-amino)-ethane in 30 ml of dry chloroform isadded dropwise, within about 20 minutes, to a solution of 3.6 g (22mmoles) of benzoyl isothiocyanate (D. T. Elmore and J. R. Ogle, loc.cit.) in 40 ml of dry acetone at room temperature. The resulting mixtureis stirred for 6 hours at room temperature, and next day it is boiledfor 2 hours. The solvents are distilled off, and the resulting semisolidsubstance, weighing 10.7 g, is triturated with 30 ml of isopropanol at50° C. 7.2 g (83.4%) of colourless, crystalline1-benzoyl-3-(2',6'-dimethylphenyl)-3-(β-/2',6'-dimethylphenyl-amino/ethyl)-thioureaare obtained; m.p.: 135°-136° C.

(b) 2.16 g (5 mmoles) of1-benzoyl-3-(2',6'-dimethylphenyl)-3-(β-/2',6'-dimethylphenyl-amino/-ethyl)-thiourea,prepared as described in point (a) above, are added to a solution of 3.0g (53.6 mmoles) of potassium hydroxide in 30 ml of water and 50 ml ofethanol, and the resulting mixture is boiled for 3 hours. The mixture iscooled and poured onto 300 ml of icy water. The separated crystallinesubstance is filtered off, washed with water, and dried at 40° to 50° C.1.31 g (80.3%) of crude1-(2',6'-dimethylphenyl)-1-(β-/2',6'-dimethylphenyl-amino/-ethyl)-thiourea,melting at 146°-148° C., are obtained. The product melts at 149°-150° C.after recrystallization from cyclohexane.

EXAMPLE 2 1,3-Bis(2',6'-dimethylphenyl)-2-imino-4-methylimidazolidine

M.p.: 124°-125° C.; yield: 84.4%.

1,2-Bis(2',6'-dimethylphenyl-amino)-propane, utilized as startingsubstance, is prepared as follows:

Method (a)

2,6-Dimethylaniline is reacted with 1,2-dibromopropane as described byShapiro et al. (loc. cit.) to obtain the aimed compound with a yield of18.6%.

Method (b)

(a) A solution of 123 ml (202 g, 1.7 moles) of thionyl chloride in 200ml of dry benzene is added dropwise to a solution of 100 g (0.558 moles)of N-(β-hydroxypropyl)-2,6-dimethyl-aniline (prepared from2,6-dimethylaniline and 1,2-epoxipropane as described in the publishedDutch patent application No. 6,507,312; b.p.: 120°-125° C./1 mm Hg;yield: 51%) in 1000 ml of dry benzene at room temperature under nitrogenatmosphere. The resulting mixture is stirred and boiled under nitrogenatmosphere for 5 hours. The mixture is cooled with icy water, 100 ml ofwater are added dropwise to the cooled mixture, and the pH of theresulting mixture is adjusted to 9 with 10 n aqueous sodium hydroxidesolution. The phases are separated from each other, and the aqueousphase is extracted thrice with 200 ml of benzene each. The organicsolutions are combined, washed thrice with 300 ml of water each, driedover anhydrous sodium sulfate, and the solvent is evaporated underreduced pressure. The residual dark brown oil is divided into two partsof about equal weights, and then distilled under reduced pressure. 85 g(77%) of N-(β-chloropropyl)-2,6-dimethyl-aniline are obtained as acolourless oil boiling at 105°-108° C./0.8 mm Hg.

(b) A mixture of 86 g (0.435 moles) ofN-(β-chloropropyl)-2,6-dimethyl-aniline, prepared as described in point(a) above, 110 ml (107.4 g, 0.88 moles) of 2,6-dimethylaniline and 4.2 g(25 mmoles) of potassium iodide is stirred at 140° to 145° C. for 3hours under nitrogen atmosphere. The mixture is allowed to cool to about80° C., 300 ml of isopropanol are added, the resulting mixture isallowed to cool to room temperature under stirring, and then allowed tostand overnight. The separated precipitate is filtered off, washed withcold (+5° C.) isopropanol and dried. 67.1 g (42.4%) of crude1,2-bis(2',6'-dimethylphenyl-amino)-propane hydrochloride (fraction A)are obtained. The filtrate is admixed with 200 ml of 20% aqueoushydrochloric acid, and the mixture is allowed to stand for 24 hours. Theseparated precipitate is filtered off, washed with water and dried. Inthis way further 48 g (34.6%) of crude1,2-bis(2',6'-dimethylphenyl-amino)propane hydrochloride (fraction B)are obtained, thus the total yield is 83.0%. Fractions A and B arecombined, dissolved in a mixture of 500 ml of dimethyl formamide and 250ml of water, and the solution is rendered alkaline (pH=10) with 10 naqueous sodium hydroxide solution. The solution is admixed with 2 litersof water, the separated precipitate is filtered off, washed with water,and dried. 87.15 g (70.9%) of1,2-bis(2',6'-dimethylphenyl-amino)-propane (m.p.: 52°-55° C.) areobtained. This product is sufficiently pure to apply it directly in thenext step.

Method (c)

(a) A mixture of 250 ml (712 g, 2.63 moles) of phosphorous tribromideand 250 ml of dry chloroform is added dropwise to a solution of 100 g(0.558 moles) of N-(β-hydroxypropyl)-2,6-dimethyl-aniline in 500 ml ofdry chloroform. During the addition the temperature of the mixture ismaintained below +25° C. by cooling with icy water. The resultingmixture is boiled for 6 hours, thereafter it is cooled on salted ice,and 100 ml of water are added dropwise. The pH of the resulting mixtureis adjusted to 9 with 10 n aqueous sodium hydroxide solutions. Thephases are separated from each other, and the aqueous phase is extractedthrice with 300 ml of chloroform each. The organic solutions arecombined, washed four times with 500 ml of water each, dried overanhydrous sodium sulfate, and the solvent is evaporated under reducedpressure. 118.2 g (87.5%) of N-(β-bromopropyl)-2,6-dimethyl-aniline areobtained as a colourless oily residue. This product is sufficiently pureto be applied directly in the next step. When distilling the oil at 0.3mm Hg it boils at 102°-106° C.

(b) A mixture of 106.8 g (0.441 moles) ofN-(β-bromopropyl)-2,6-dimethyl-aniline, obtained as described in point(a) above, 110 ml (107.4 g, 0.88 moles) of 2,6-dimethylaniline and 1.6 g(10 mmoles) of potassium iodide is stirred at 100° to 105° C. for 3hours under nitrogen atmosphere. The mixture is allowed to cool, 600 mlof 10% aqueous hydrochloric acid are added, and the resulting mixture isallowed to stand at room temperature overnight. The separatedprecipitate, which is a mixture of the hydrochloride and thehydrobromide of the expected product, is filtered off, washed withwater, dried, and then treated as described in point (b) of Method (b)above in order to liberate the base. In this way 93.8 g (75.3%) of1,2-bis(2',6'-dimethylphenyl-amino)-propane are obtained; m.p.: 54°-56°C.

Method (d)

A solution of 4.8 ml (7.1 g, 0.062 moles) of methanesulfonyl chloride in10 ml of 1,2-dichloroethane is added dropwise, at 5° to 10° C., to astirred solution of 10.0 g (0.0556 moles) ofN-(β-hydroxypropyl)-2,6-dimethyl-aniline and 8.5 ml (6.2 g, 0.0612moles) of triethylamine in 50 ml of 1,2-dichloroethane. The mixture isstirred for additional 30 minutes at 5° to 10° C., thereafter theseparated triethylamine salt is filtered off, washed with1,2-dichloroethane, and the filtrate is added dropwise, under nitrogenatmosphere, to a stirred solution of 13.9 ml (13.6 g, 0.112 moles) of2,6-dimethylaniline in 20 ml of 1,2-dichloroethane at 80° to 85° C. Theresulting mixture is stirred and boiled for a further hour, thereafterit is cooled, the separated salt of 2,6-dimethylaniline is filtered off,and the filtrate is evaporated under reduced pressure. 150 ml of 1 naqueous hydrochloric acid are added to the thick, oily residue, and themixture is stirred for one hour. The separated crude solid, which is thehydrochloride of the expected product, is filtered off, washed withwater, and dried. 13.5 g of the crude hydrochloride are obtained. Thissalt is treated as described in point (b) of Method (b) above in orderto liberate the base. 9.4 g (60%) of1,2-bis(2',6'-dimethylphenyl-amino)propane are obtained; m.p.: 53°-55°C.

EXAMPLE 3 1,3-Bis(2',6'-dimethylphenyl)-2-imino-4-n-butylimidazolidineEXAMPLE 41,3-Bis(2',6'-dimethylphenyl)-2-imino-4-trifluoromethyl-imidazolidineEXAMPLE 51,3-Bis(2',6'-dimethylphenyl)-2-imino-4-hydroxymethyl-imidazolidine

M.p.: 244°-245° C.; yield: 96.8%.

2,3-Bis(2',6'-dimethylphenyl-amino)-1-propanol, applied as startingsubstance, is prepared as follows:

A mixture of 109 g (0.5 moles) of 2,3-dibromo-propan-1-ol, 248 ml (242.4g, 2.0 moles) of 2,6-dimethylaniline and 1.0 g (6 mmoles) of potassiumiodide is stirred at 140° to 145° C. for 3 hours under nitrogenatmosphere. The mixture is allowed to cool to about 80° C., and 100 mlof isopropanol, followed by 500 ml of 20% aqueous hydrochloric acid, areadded. The mixture is allowed to stand overnight, thereafter theseparated precipitate is filtered off, washed with water and dried. Theresulting solid, weighing 170 g, is dissolved in 1500 ml of methanol,the pH of the solution is adjusted to 10 with 10 n aqueous sodiumhydroxide solution, and the mixture is diluted with 1500 ml of water.The separated precipitate is filtered off, washed with water and dried.99 g (66.4%) of crude 2,3-bis(2',6'-dimethylphenylamino)-1-propanol areobtained. The product melts at 92°-94° C. after recrystallization frommethanol.

EXAMPLE 61,3-Bis(2',6'-dimethylphenyl)-2-imino-4,4-dimethylimidazolidine

M.p.: 171°-174° C.; yield: 38.9%.

1,2-Bis(2',6'-dimethylphenyl-amino)-2-methyl-propane, applied asstarting substance, is prepared as follows:

(a) A mixture of 7.0 g (0.037 moles) ofN-methacryloyl-2,6-dimethyl-aniline (prepared e.g. by acylating2,6-dimethylaniline with methacryloyl chloride in diethyl ether; m.p.:110°-112° C.) and 9.3 ml (9.1 g, 0.075 moles) of 2,6-dimethylaniline ismaintained at 220° C. for 2 hours under nitrogen atmosphere. The mixtureis allowed to cool and then triturated with 80 ml of 1 n aqueoushydrochloric acid. The separated crystalline crude product is filteredoff, washed with water and dried. The crude product is dissolved in 200ml of hot isopropanol, the insolubles are filtered off, and the filtrateis allowed to cool. The separated crystalline substance is filtered off,washed with isopropanol and dried, 4.0 g ofN-(α-/2,6-dimethylphenyl-amino/-isobutyryl)-2,6-dimethyl-aniline areobtained. The filtrate is concentrated to a volume of about 20 ml.Further 1.1 g of the above substance separate from the concentrate, thusa total amount of 5.1 g (44.3%) ofN-(α-/2,6-dimethylphenyl-amino/-isobutyryl)-2,6-dimethylaniline areobtained; m.p.: 141°-143° C.

(b) A solution of 4.0 g (0.0129 moles) ofN-(α-/2,6-dimethylphenyl-amino/-isobutyryl)-2,6-dimethyl-aniline,prepared as described in point (a) above, in 40 ml of drytetrahydrofuran is added dropwise at 5° to 10° C. to 24 ml of a stirred1.68 molar borane solution in tetrahydrofuran. The resulting mixture isstirred and boiled for 4 hours. Thereafter the mixture is cooled, 8 mlof the above borane solution are added, and boiling is continued foradditional 4 hours. The mixture is cooled on an ice bath, 25 ml of 20%aqueous hydrochloric acid are added dropwise, and tetrahydrofuran isevaporated under reduced pressure. The residual aqueous mixture isdiluted with 200 ml of water, rendered alkaline with 5 n aqueous sodiumhydroxide solution, and then extracted thrice with 70 ml of diethylether each. The etheral solutions are combined, washed thrice with 20 mlof water each, dried over anhydrous magnesium sulfate, and the solventis evaporated under reduced pressure. The oily residue is trituratedwith diisopropyl ether to obtain 1.8 g of the unreacted starting amideas a crystalline substance. This substance is filtered off and thefiltrate is evaporated under reduced pressure. The crude1,2-bis(2',6'-dimethylphenyl-amino)-2-methyl-propane is obtained with aquantitative yield calculated for the amide converted. The product ispurified through its hydrochloride (m.p.: 150°-152° C.). The pure basemelts at 30°-31° C.

EXAMPLE 71,3-Bis(2',6'-dimethylphenyl)-2-imino-4,5-cis-dimethylimidazolidine

M.p.: 220°-221° C. (fumarate); yield: 49.1%

Meso-2,3-bis(2',6'-dimethylphenyl-amino)-butane, applied as startingsubstance to prepare the above compound, furthermore racemic2,3-bis(2',6'-dimethylphenyl-amino)-butane, applied as startingsubstance to prepare the compound of Example 11, are produced asfollows:

(a) A mixture of 37.2 ml (36.3 g, 0.3 moles) of 2,6-dimethylaniline,13.1 ml (12.9 g, 0.15 moles) of 2,3-butanedione and 100 ml of ethanol isboiled for 12 hours. The solvent is evaporated under reduced pressure,80 ml of water and 20 ml of acetic acid are added to the residue, andthe resulting mixture is stirred for 6 hours at 0° to +5° C. The mixtureis allowed to stand overnight, thereafter the separated precipitate isfiltered off, washed with water and dried. 34.0 g (77.5%) of crude2,3-bis(2',6'-dimethylphenyl-imino)butane are obtained; m.p.: 78°-86° C.After recrystallization from ethanol 25.1 g (57.2%) of the puresubstance, melting at 88°-90° C., are obtained.

(b) 11.6 g (0.308 moles) of solid sodium borohydride are added in smallportions, within about 0.5 hours, to a vigorously stirred suspension of30 g (0.103 moles) of 2,3-bis(2',6'-dimethylphenyl-imino)-butane in 600ml of methanol at room temperature. The resulting mixture is stirred andboiled for one hour, then it is cooled to room temperature, further 11.6g of solid sodium borohydride are added as described above, and boilingis continued for an additional hour. The solvent is evaporated underreduced pressure, the residue is admixed with 200 ml of water, and theresulting mixture is extracted thrice with 200 ml of benzene each. Thebenzene solutions are combined, dried over anhydrous potassiumcarbonate, and the solvent is evaporated under reduced pressure. Theresidue, weighing 31.3 g, is dissolved in 500 ml of isopropanol, 100 mlof isopropanolic hydrochloric acid (containing about 15 g of acid/100ml) are added, and the mixture is allowed to stand at 0° C. for 2 hours.The separated precipitate is filtered off, washed with cold isopropanoland dried. 26.4 g of the hydrochloride of the expected product areobtained.

The hydrochloride obtained as described above is dissolved in 300 ml ofdimethylformamide, the solution is rendered alkaline with concentratedaqueous ammonia, diluted with 1 liter of water, and the mixture isextracted thrice with 200 ml of diethyl ether each. The organicsolutions are combined, washed thrice with 100 ml of water each, driedover anhydrous potassium carbonate, filtered, and the solvent isevaporated. 18.8 g (61.8%) of the product, consisting of a mixture ofmeso and racemic 2,3-bis(2',6'-dimethylphenyl-amino)-butane, areobtained.

This isomeric mixture is subjected to chromatography on a column filledwith 500 g of silica gel, applying a 8:1 mixture of benzene and ethylacetate as eluting agent. The following substances are obtained: 10 g(32.9%) of meso-2,3-bis(2',6'-dimethylphenyl-amino)-butane; R_(f) =0.9,m.p.: 100°-101° C. (after recrystallization from hexane), and 6.4 g(21.1%) of racemic 2,3-bis(2',6'-dimethylphenyl-amino)-butane; R_(f)=0.75, m.p.: 41°-43° C. (after recrystallization from petroleum ether).

EXAMPLE 81,3-Bis(2',6'-dimethylphenyl)-2-imino-4,5-transdimethyl-imidazolidine

M.p.: 155°-157° C. (fumarate); yield: 58.2%.

Racemic 2,3-bis(2',6'-dimethylphenyl-amino)-butane, applied as startingsubstance, is prepared as described in Example 10.

EXAMPLE 9 1,3-Bis(2',3'-dimethylphenyl)-2-imino-imidazolidine

M.p.: 123°-125° C.; yield: 54.2%.

1,2-Bis(2',3'-dimethylphenyl-amino)-ethane, applied as startingsubstance, is prepared by the method of Shapiro et al. (loc. cit.),modified as indicated below:

246 ml (242.4 g, 2.0 moles) of 2,3-dimethylaniline are added dropwise,within 1.5 hours, to a stirred and boiled solution of 43 ml (94 g, 0.5moles) of 1,2-dibromoethane in 500 ml of xylene. After the addition themixture is stirred for one hour at 140° C. and then allowed to stand.Next day the separated precipitate is filtered off, washed with benzeneand dried. 259.3 g of the hydrobromide of the expected compound(fraction A) are obtained. The filtrate is evaporated in vacuo, theresidue is triturated with isopropanol, the separated precipitate isfiltered off, washed with cold isopropanol and dried. Additional 30 g ofthe above compound (fraction B) are obtained. Fractions A and B arecombined, dissolved in 1000 ml of dimethylformamide, the solution isrendered alkaline with a 10 n aqueous sodium hydroxide solution understirring and cooling with ice, and then diluted with 2 liters of water.The separated precipitate is filtered off, washed with water and dried.84.3 g (62.8%) of 1,2-bis(2',3'-dimethylphenyl-amino)-ethane areobtained; m.p.: 130°-133° C.

EXAMPLE 10 1,3-Bis(2',3'-dimethylphenyl)-2-imino-4-methylimidazolidine

M.p.: 162°-164° C.; yield: 59.2%. The given melting point relates to thedifumarate.

1,2-Bis(2',3'-dimethylphenyl-amino)-propane, applied as startingsubstance, is prepared as follows:

(a) 2,3-Dimethylaniline is reacted with 1,2-epoxypropane as described inExample 3, Method (b), point (a) to obtainN-(β-hydroxypropyl)-2,3-dimethylaniline; b.p.: 153°-155° C./1 mm Hg,yield: 71.8%.

(b) N-(β-Hydroxypropyl)-2,3-dimethyl-aniline, prepared as indicated inpoint (a) above, is converted intoN-(β-bromopropyl)-2,3-dimethyl-aniline as described in Example 3, Method(c), point (a). The product, boiling at 134°-136° C./1 mm Hg, isobtained with a yield of 65.1%.

(c) N-(β-Bromopropyl)-2,3-dimethyl-aniline, prepared as indicated inpoint (b) above, is reacted with 2,3-dimethylaniline as given in Example3, Method (c), point (b) to obtain1,2-bis(2',3'-dimethylphenyl-amino)-propane with a yield of 84.2%. Thehydrobromide of the product melts at 204°-208° C.

EXAMPLE 111-(2',6'-Dimethylphenyl)-2-imino-3-(2',3'-dimethylphenyl)-4-methyl-imidazolidine

M.p.: 186°-188° C. (difumarate); yield: 95.4%.

1-(2',6'-dimethylphenyl-amino)-2-(2',3'-dimethylphenyl-amino)-propane,applied as starting substance, is prepared as follows:

A mixture of 29.5 g (0.15 moles) ofN-(β-chloropropyl)-2,6-dimethyl-aniline, prepared as described inExample 3, Method (b), point (a), 37.2 ml (36.3 g, 0.3 moles) of2,3-dimethylaniline and 0.5 g (3 mmoles) of potassium iodide is stirredat 100° to 105° C. for 3 hours under nitrogen atmosphere. The mixture isallowed to cool, admixed with 30 ml of isopropanol, the separatedprecipitate is filtered off, washed with cold isopropanol and dried. Inthis way 14.25 g (30.2%) of 2,3-dimethylaniline hydrochloride areseparated. The filtrate is admixed with 200 ml of water, the mixture isacidified with 20% aqueous hydrochloric acid, the separated precipitateis filtered off, washed with water and dried. 30.2 g (56.7%) of1-(2',6'-dimethylphenyl-amino)-2-(2',3'-dimethylphenyl-amino)propanedihydrochloride are obtained. This salt is treated as described inExample 3, Method (b) point (c) to obtain the free base. The base isisolated by extracting the mixture with chloroform. The resultingsubstance is an oil at room temperature.

EXAMPLE 121-(2',3'-Dimethylphenyl)-2-imino-3-(2',6'-dimethylphenyl)-4-methyl-imidazolidine

M.p.: 165°-167° C. (difumarate); yield: 54.6%.

1-(2',3'-Dimethylphenyl-amino)-2-(2',6'-dimethylphenyl-amino)-propane,applied as starting substance, is prepared as follows:

N-(β-Bromopropyl)-2,3-dimethyl-aniline, prepared as described in Example13, point (b), is reacted with 2,6-dimethylaniline as described inExample 3, Method (c), point (b) to obtain the desired substance with ayield of 29.0%. The hydrochloride of the base melts at 182°-184° C.

EXAMPLE 131,3-Bis(2',4',6'-trimethylphenyl)-2-imino-4-methylimidazolidine

M.p.: 188°-189° C.; yield: 71.0%.

1,2-Bis(2',4',6'-trimethylphenyl-amino)-propane, applied as startingsubstance, is prepared as follows:

(a) 2,4,6-Trimethylaniline is reacted with 1,2-epoxypropane as describedin Example 3, Method (b), point (a) to obtainN-(β-hydroxy-propyl)-2,4,6-trimethyl-aniline with a yield of 45.1%,b.p.: 130°-135° C./0.4 mm Hg.

(b) N-(β-Hydroxypropyl)-2,4,6-trimethyl-aniline, prepared as indicatedin point (a) above, is treated as described in Example 3, Method (b),point (a) to obtain N-(β-chloropropyl)-2,4,6-trimethyl-aniline with ayield of 87.6%; b.p.: 110°-118° C./0.3 mm Hg.

(c) 32.75 g (0.155 moles) of N-(β-chloropropyl)-2,4,6-trimethyl-aniline,prepared as indicated in point (b) above, are reacted with 41.8 g (0.31moles) of 2,4,6-trimethylaniline in the presence of 1.0 g (6 mmoles) ofpotassium iodide as described in Example 3, Method (b), point (b). Theresulting mixture is admixed with 50 ml of diethyl ether, the separatedprecipitate is filtered off, washed with diethyl ether and dried. 24.8 g(46.6%) of 2,4,6-trimethylaniline hydrochloride are obtained. Thefiltrate is acidified with isopropanolic hydrochloric acid (acidcontent: about 15 g/100 ml), and the resulting mixture is maintained at0° to +5° for 2 hours. The separated precipitate is filtered off, washedwith cold isopropanol, and dried. 50.3 g (84.8%) of1,2-bis(2',4',6'-trimethylphenyl-amino)-propane dihydrochloride areobtained; m.p.: 172°-173° C. The base is liberated from this salt asdescribed in Example 3, Method (b), point (b), and is separated from thereaction mixture by chloroform extraction.

EXAMPLE 141-(2',6'-Dimethylphenyl)-2-imino-3-(2',4',6'-trimethylphenyl)-4-methyl-imidazolidine

M.p.: 147.5°-150° C.; yield: 63.7%.

1-(2',6'-Dimethylphenyl-amino)-2-(2',4',6'-trimethylphenyl-amino)-propane,applied as starting substance, is prepared by reactingN-(β-chloropropyl)-2,6-dimethyl-aniline, a compound prepared accordingto Example 3, Method (b), point (a), with 2,4,6-trimethylaniline underthe conditions specified in Example 16, point (c). The aimed compound isobtained with a yield of 87.6%; m.p.: 128°-130° C. (dihydrochloride).

EXAMPLE 151-(2',4',6'-Trimethylphenyl)-2-imino-3-(2',6'-dimethylphenyl)-4-methyl-imidazolidine

M.p.: 191°-193° C.; yield: 83.9%.

1-(2',4',6'-Trimethylphenyl-amino)-2-(2',6'-dimethylphenyl-amino)-propane,applied as starting substance, is obtained with a yield of 65.6% byreacting N-(β-chloropropyl)-2,4,6-trimethyl-aniline, a compound preparedaccording to Example 16, point (b), with 2,6-dimethylaniline under theconditions given in Example 16, point (c). The hydrochloride of theproduct melts at 174°-177° C.

EXAMPLE 16 1,3-Bis(2',6'-diethylphenyl)-4-methyl-imidazolidine

M.p.: 143°-145° C. (hydrochloride); yield: 44.8%.

1,2-Bis(2',6'-diethylphenylamino)-propane, applied as startingsubstance, is prepared as follows:

(a) 2,6-Diethylaniline is reacted with 1,2-epoxypropane as described inExample 3, Method (b), point (a) to obtainN-(β-hydroxypropyl)-2,6-diethylaniline with a yield of 44.7%; b.p.:137°-145° C./1 mm Hg.

(b) N-(β-Hydroxypropyl)-2,6-diethyl-aniline, obtained as indicated inpoint (a) above, is treated as described in Example 3, Method (b), point(a) to obtain N-(β-chloropropyl)-2,6-diethyl-aniline with a yield of69.1%; b.p.: 114°-120° C./1 mm Hg.

(c) A mixture of 46.3 g (0.205 moles) ofN-(β-chloropropyl)-2,6-diethyl-aniline, obtained as indicated in point(b) above, 61.2 g (0.41 moles) of 2,6-diethylaniline and 1.66 g (10mmoles) of potassium iodide is stirred at 140° to 145° C. for 4 hoursunder nitrogen atmoshere. The mixture is allowed to cool, 150 ml ofisopropanol are added, and the resulting mixture is stirred at 0° to +5°C. for 2 hours. The separated 2,6-diethyleniline hydrochloride (19.2 g,25.2%) is filtered off, washed with cold isopropanol and dried. Thefiltrate is acidified with isopropanolic hydrochloric acid (acidcontent: about 15 g/100 ml), the separated precipitate is filtered off,washed with cold isopropanol and dried. The resulting crude substance,weighing 72 g, is recrystallized from methanol to obtain 29.4 g (34.8%)of 1,2-bis(2',6'-diethylphenyl-amino)-propane dihydrochloride as auniform substance; m.p.: 161°-167° C. The base is liberated from thissalt as described in point (c) of Example 16 and isolated from thereaction mixture by extraction with chloroform.

EXAMPLE 17 1,3-Bis(4'-methoxyphenyl)-2-imino-imidazolidine

M.p.: 194°-195° C.; yield: 91.0%.

1,2-Bis(4'-methoxyphenyl-amino)-propane, applied as starting substance,can be prepared e.g. by the method of McKay and Tarlton (loc. cit.) witha yield of 91.0% (yield reported in the literature: 97.9%).

EXAMPLE 18 1,3-Bis(4'-methoxyphenyl)-2-imino-4-methyl-imidazolidine

M.p.: 154°-156° C.; yield: 85.5%.

1,2-Bis(4'-methoxyphenyl-amino)-propane, applied as starting substance,is obtained with a yield of 32.7% by reacting 4-methoxyaniline with1,2-dibromopropane as described by McKay and Tarlton (loc. cit.). Thecompound melts at 82°-84° C.

EXAMPLE 191-(2',6'-Dimethylphenyl)-2-imino-3-(4'-methoxyphenyl)-4-methyl-imidazolidine

M.p.: 150°-152° C. (difumarate); yield: 61.2%.

1-(2',6'-Dimethylphenyl-amino)-2-(4'-methoxyphenylamino)-propane appliedas starting substance, is prepared by reactingN-(β-chloropropyl)-2,6-dimethyl-aniline, a compound obtained asdescribed in Example 3, Method (b), point (a), with 4-methoxyaniline.The reaction is performed as described in Example 16, point (c), withthe difference that the temperature is 100° to 105° C., and crystalline4-methoxyaniline hydrochloride is removed from the mixture bytriturating it with ethyl acetate. The product, melting at 160°-170° C.(dihydrochloride), is obtained with a yield of 64.0%.

EXAMPLE 201,3-Bis(3'-trifluoromethylphenyl)-2-imino-4-methylimidazolidine

M.p.: 67°-69° C.; yield: 44.4%.

1,2-Bis(3'-trifluoromethylphenyl-amino)-propane, applied as startingsubstance, is prepared as follows:

(a) 3-Trifluoromethylaniline is reacted with 1,2-epoxypropane asdescribed in Example 3, Method (b), point (a) to obtainN-(β-hydroxypropyl)-3-trifluoromethyl-aniline with a yield of 61.5%;b.p.: 112°-118° C./0.5 mm Hg.

(b) N-(β-Hydroxypropyl)-3-trifluoromethyl-aniline, prepared as indicatedin point (a) above, is treated as described in Example 3, Method (b),point (a) to obtain N-(β-chloropropyl)-3-trifluoromethyl-aniline with ayield of 81.0%; b.p.: 102°-103° C./0.4 mm Hg.

(c) N-(β-chloropropyl)-3-trifluoromethyl-aniline is reacted with3-trifluoromethylaniline as described in Example 16, point (c) to obtain1,2-bis(3'-trifluoromethylphenyl-amino)propane with a yield of 76.6%.The dihydrochloride of this base melts at 116°-120° C.

EXAMPLE 211-(2',6'-Dimethylphenyl)-2-imino-3-(3'-trifluoromethylphenyl)-4-methyl-imidazolidine

M.p.: 86°-90° C. (fumarate); yield: 80.6%.

1-(2',6'-Dimethylphenyl-amino)-2-(3'-trifluoromethylphenyl-amino)-propane,applied as starting substance, is prepared by reactingN-(β-chloropropyl)-2,6-dimethyl-aniline, a compound prepared asdescribed in Example 3, Method (b), point (a), with3-trifluoromethyl-aniline. The reaction is performed as described inExample 16, point (c) with the difference that crystalline3-trifluoromethyl-aniline hydrochloride is separated from the reactionmixture by trituration with benzene. The aimed product is obtained witha yield of 42.4%; m.p.: 160°-166° C. (dihydrochloride).

EXAMPLE 221-(3'-Trifluoromethylphenyl)-2-imino-3-(2',6'-dimethylphenyl)-4-methyl-imidazolidine

M.p.: 146°-149° C. (fumarate); yield: 28.4%.

1-(3'-Trifluoromethylphenyl-amino)-2-(2',6'-dimethylphenyl-amino)-propane,applied as starting substance, is prepared by reactingN-(β-chloropropyl)-3-trifluoromethylaniline, a compound obtained asdescribed in Example 23, point (b), with 2,6-dimethylaniline. Thereaction is performed as described in Example 16, point (c) with thedifference that crystalline 2,6-dimethylaniline hydrochloride isseparated from the reaction mixture by trituration with ethyl acetate.The aimed product is obtained with a yield of 55.6%; m.p.: 95°-98° C.(dhydrochloride).

EXAMPLE 231-(2'-Chloro-6'-methyl-phenyl)-2-imino-3-(2',6'-dimethylphenyl)-4-methyl-imidazolidine

M.p.: 173°-175° C. (fumarate); yield: 40.5%

1-(2'-Chloro-6'-methyl-phenyl-amino)-2-(2',6'-dimethylphenyl-amino)-propane,applied as starting substance, is prepared as follows:

(a) 2-Chloro-6-methyl-aniline is reacted with 1,2-epoxypropane asdescribed in Example 3, Method (b), point (a) to obtainN-(β-hydroxypropyl)-2-chloro-6-methyl-aniline with a yield of 30.1%;b.p.: 118°-122° C./0.2 mm Hg.

(b) N-(β-Hydroxypropyl)-2-chloro-6-methyl-aniline, obtained as indicatedin point (a) above, is treated as described in Example 3, Method (b),point (a) to obtain N-(β-chloropropyl)-2-chloro-6-methyl-aniline with ayield of 83.4%; b.p.: 106°-108° C./0.7 mm Hg.

(c) N-(β-Chloropropyl)-2-chloro-6-methyl-aniline, obtained is describedin point (b) above, is reacted with 2,6-dimethylaniline as described inExample 16, point (c), and the free base is distilled under reducedpressure.1-(2'-Chloro-6'-methyl-phenyl-amino)-2-(2',6'-dimethylphenyl-amino)-propaneis obtained with a yield of 24.2%; b.p.: 177°-180° C./0.4 mm Hg.

EXAMPLE 24 1,3-Bis(4'-chlorophenyl)-2-imino-4-methyl-imidazolidine

M.p.: 117°-119° C.; yield: 76.5%.

1,2-Bis(4'-chlorophenyl-amino)-propane, applied as starting substance,is prepared as follows:

(a) 4-Chloroaniline is reacted with 1,2-epoxypropane as described inExample 3, Method (b), point (a) to obtainN-(β-hydroxypropyl)-4-chloro-aniline with a yield of 61.0%; b.p.:158°-164° C./0.3 mm Hg.

(b) N-(β-Hydroxypropyl)-4-chloro-aniline, obtained as indicated in point(a) above, is treated as described in Example 3, Method (b), point (a)to obtain N-(β-chloropropyl)-4-chloro-aniline with a yield of 50.0%;b.p.: 120°-123° C./0.4 mm Hg.

(c) N-(β-Chloropropyl)-4-chloro-aniline, obtained as indicated in point(b) above, is reacted with 4-chloroaniline as described in Example 16,point (c) to obtain 1,2-bis(4'-chlorophenyl-amino)-propane with a yieldof 84.9%. The product melts at 77°-80° C.

EXAMPLE 231-(2',6'-Dimethylphenyl)-2-imino-3-(4'-chlorophenyl)-4-methyl-imidazolidine

M.p.: 168°-171° C. (fumarate); yield: 64.1%.

1-(2',6'-Dimethylphenyl-amino)-2-(4'-chlorophenylamino)-propane, appliedas starting substance, is prepared as follows:

A mixture of 28.2 g (0.143 moles) ofN-(β-chloropropyl)-2,6-dimethylaniline, prepared as described in Example3, Method (b), point (a), 36.4 g (0.285 moles) of 4-chloroaniline and1.6 g (10 mmoles) of potassium iodide is stirred at 140° to 145° C. for3 hours under nitrogen atmosphere. The mixture is allowed to cool toabout 60° C., and 30 ml of ethyl acetate are added. The mixture iscooled to room temperature, and the separated precipitate is filteredoff, washed with ethyl acetate and dried. 14.0 g of1-(2',6'-dimethyl-phenylamino)-2-(4'-chlorophenyl-amino)-propanehydrochloride (fraction A) are obtained. The filtrate is acidified withisopropanolic hydrochloric acid (acid content: about 15 g/100 ml), theseparated precipitate is filtered off, washed with isopropanol anddried. 28.8 g of the same compound (fraction B) are obtained. FractionsA and B are combined, triturated with 100 ml of water, filtered, washedwith water, dried, and the resulting solid, weighing 25.7 g, isrecrystallized from methanol. 21.4 g (46.0%) of pure1-(2',6'-dimethylphenylamino)-2-(4'-chlorophenyl-amino)-propanehydrochloride are obtained; m.p.: 170°-176° C. This salt is converted tothe free base as described in Example 3, Method (b), point (b), and thebase is separated by extracting the reaction mixture with chloroform.

EXAMPLE 261-(4'-Chlorophenyl)-2-imino-3-(2',6'-dimethylphenyl)-4-methyl-imidazolidine

M.p.: 155°-157° C. (difurmarate); yield: 43.9%.

1-(4'-Chlorophenyl-amino)-2-(2',6'-dimethylphenylamino)-propane, appliedas starting substance, is obtained with a yield of 50.9% by reactingN-(β-chloropropyl)-4-chloro-aniline, a compound prepared as described inExample 27, point (b), with 2,6-dimethylaniline according to the methodgiven in Example 25, point (a). The hydrochloride of the product meltsat 170°-178° C.

EXAMPLE 271-(2',3'-Dimethylphenyl)-2-imino-3-(4'-chlorophenyl)-4-methyl-imidazolidine

M.p.: 82°-84° C.; yield: 82.6%.

1-(2',3'-Dimethylphenyl-amino)-2-(4'-chlorophenylamino)-propane, appliedas starting substance, is prepared as follows:N-(β-bromopropyl)-2,3-dimethyl-aniline, obtained as described in Example13, point (b), is reacted with 4-chloroaniline. The reaction isperformed as described in Example 3, Method (c), point (b) with thedifference that isopropanolic hydrochloric acid is substituted foraqueous hydrochloric acid. The resulting hydrochloride, melting at147°-151° C., is treated as described in Example 6, point (a) to obtainthe free base with a yield of 35.9%; m.p.: 55°-58° C.

EXAMPLE 281-(2',6'-Dimethylphenyl)-2-imino-3-phenyl-4-methylimidazolidine

M.p.: 190°-195° C. (hydrobromide); yield: 52.3%.

1-(2',6'-Dimethylphenyl)-2-phenyl-amino-propane, applied as startingsubstance, is prepared with a yield of 41.0% by reactingN-(β-bromopropyl)-2,6-dimethyl-aniline, a compound obtained as describedin Example 3, Method (c), point (a), with aniline according to theprocess given in Example 3, Method (c), point (b). The boiling point ofthe product is 116°-120° C./1.5 mm Hg.

EXAMPLE 291,3-Bis(2',6'-dimethylphenyl)-2-acetimino-4-acetoxymethyl-imidazolidine

The title compound, melting at 163°-164° C., is obtained with a yield of87.7% from1,3-bis(2',6'-dimethylphenyl)-2-imino-4-hydroxymethyl-imidazolidine,prepared as described in Example 6.

EXAMPLE 301,3-Bis(2',6'-dimethylphenyl)-2-acetimino-4-hydroxymethyl-imidazolidine

A solution of 7.0 g (175 mmoles) of sodium hydroxide in 100 ml ofethanol is added in a single portion to a solution of 7.0 g (17.2mmoles) of1,3-bis(2',6'-dimethylphenyl)-2-acetimino-4-acetoxymethyl-imidazolidine,prepared as described in Example 29, in 50 ml of ethanol at roomtemperature. The reaction mixture is stirred at room temperature for onehour, thereafter it is poured into 300 ml of icy water, and extractedfour times with 100 ml of chloroform each. The organic solutions arecombined, washed thrice with 100 ml of water each, dried over anhydroussodium sulfate, and the solvent is evaporated under reduced pressure.The residue is recrystallized from dioxane. 5.8 g (92.1%) of1,3-bis(2',6'-dimethylphenyl)-2-acetimino-4-hydroxymethylimidazolidineare obtained; m.p.: 194°-196° C.

EXAMPLE 311,3-Bis(2',6'-dimethylphenyl)-2-carbethoxyimino-4-hydroxymethyl-imidazolidine

The title compound is prepared from1,3-bis(2',6'-dimethylphenyl)-2-imino-4-hydroxymethyl-imidazolidine,obtained as described in Example 6.

EXAMPLE 321,3-Bis(2',6'-dimethylphenyl)-2-acetimino-imidazolidine-4-carboxylicacid

A solution of 1.0 g (25 mmoles) of sodium hydroxide in 250 ml of wateris added to a suspension of 5.0 g (13.7 mmoles) of1,3-bis(2',6'-dimethylphenyl)-2-acetimino-4-hydroxymethyl-imidazolidine,obtained as described in Example 31, in 150 ml of dioxane. 11.0 g (69.6mmoles) of solid potassium permanganate are added to the mixture insmall portions, within about 4 hours, at room temperature, and theresulting mixture stirred for additional 2 hours at room temperature.Thereafter the mixture is allowed to stand at room temperatureovernight. Next day the separated manganese dioxide is filtered off,washed with water, and the filtrate is extracted thrice with 100 ml ofchloroform each. The chloroform solutions are combined, dried overanhydrous sodium sulfate, and the solvent is evaporated under reducedpressure. In this way 1.05 g (21.0%) of unreacted starting substance arerecovered. The pH of the extracted aqueous phase is adjusted to 4 with20% aqueous hydrochloric acid, and the acidic solution is extractedthrice with 100 ml of chloroform each. The organic solutions arecombined, dried over anhydrous sodium sulfate, the solvent is evaporatedunder reduced pressure, and the residue is triturated with diethylether. The separated precipitate is filtered off, washed with diethylether, and dried. 3.0 g (57.7%, or, calculated for the convertedstarting substance, 73.2%) of1,3-bis(2',6'-dimethylphenyl)-2-acetimino-imidazolidine-4-carboxylicacid are obtained. This crude product, melting at 210°-217° C., issufficiently pure to subject it to subsequent reactions.

EXAMPLE 331,3-Bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-carboxylic acid

A mixture of 8.0 g (21.1 mmoles) of1,3-bis(2',6'-dimethylphenyl)-2-acetimino-imidazolidine-4-carboxylicacid, obtained as described in Example 32, and 200 ml of 1 n aqueoushydrochloric acid is heated on a steam bath for 3 hours, and then themixture is allowed to standd at +5° C. overnight. Next day the separatedprecipitate is filtered off, washed with cold 1 n aqueous hydrochloricacid, and dried. 2.2 g of1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-carboxylic acidhydrochloride are obtained. Thus crude salt, melting at 288°-292° C., issufficiently pure to subject it to further reactions. Afterrecrystallization from 1 n aqueous hydrochloric acid the product meltsat 316°-318° C. The aqueous acidic solution is concentrated to obtainfurther 4.4 g of the product (m.p.: 246°-256° C.), which isrecrystallized from 1 n aqueous hydrochloric acid to obtain 2.9 g of apractically pure substance, melting at 292°-296° C. The pure compound isobtained with a total yield of 71.8%.

EXAMPLE 34 Methyl1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-carboxylate

Dry, gaseous hydrochloric acid is introduced into a solution of 1.7 g(4.55 mmoles) of1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-carboxylic acidhydrochloride, obtained as described in Example 33, in 20 ml of drymethanol at 0° to +5° C. After one hour the introduction of the gas isstopped, and the mixture is allowed to stand at +5° C. for 24 hours. Thefluffy insolubles floating in the solution are filtered off, and thesolvent is evaporated in vacuo. The residue is triturated with drydiethyl ether, the separated precipitate is filtered off, washed withdiethyl ether, and dried. 1.6 g (90.9%) of1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-carboxylic acidmethylester hydrochloride are obtained as a colourless, hygroscopiccrystalline substance; m.p.: 113°-115° C. (in sealed tube).

EXAMPLE 351,3-Bis(2',6'-dimethylphenyl)-2-acetimino-4-chloromethyl-imidazolidine

5.4 g (42.1 mmoles) of freshly prepared solidchloromethylene-dimethyl-ammonium chloride (see D. R. Hepburn and H. R.Hudson, J. Hudson, J. Chem. Soc., Perkin I. 1976 154 are added in someportions, within about 5 minutes, to a suspension of 10.2 g (27.9mmoles) of1,3-bis(2',6'-dimethylphenyl)-2-acetimino-4-hydroxymethyl-imidazolidine,obtained as described in Example 34, in 100 ml of dry acetonitrile atroom temperature. The reaction mixture is boiled for 3 hours, and thenallowed to stand overnight. The solution is concentrated to a finalvolume of about 30 ml, this concentrate is diluted with 200 ml of water,rendered alkaline with 2 n aqueous ammonia, and extracted thrice with100 ml of chloroform each. The chloroform solutions are combined, washedthrice with 50 ml of water each, dried over anhydrous potassiumcarbonate, and the solvent is evaporated. The residue is triturated with30 ml of diethyl ether to obtain 8.0 g (74.7%) of1,3-bis(2',6'-dimethylphenyl)-2-acetimino-4-chloromethyl-imidazolidine.This crude product, melting at 142°-145° C., is sufficiently pure tosubject it to further conversions. After recrystallization fromcyclohexane the product melts at 147°-149° C.

EXAMPLE 361,3-Bis(2',6'-dimethylphenyl)-2-imino-4-chloromethylimidazolidine

A mixture of 4.0 g (10.4 mmoles) of1,3-bis(2',6'-dimethylphenyl)-2-acetimino-4-chloromethyl-imidazolidine,obtained as described in Example 35, and 20 ml of 20% aqueoushydrochloric acid is heated on a steam bath for 1.5 hours. The solventis evaporated under reduced pressure, 20 ml of ethanol are added to theresidue, and the mixture is evaporated. This latter operation isrepeated once again. The residue is crystallized from a mixture of dryacetone and diisopropyl ether to obtain 3.55 g (90.3%) of1,3-bis(2',6'-dimethylphenyl)-2-imino-4-chloromethyl-imidazolidinehydrochloride; m.p.: 296°-298° C. (in sealed tube; decomposition).

EXAMPLE 371,3-Bis(2',6'-dimethylphenyl)-2-imino-4-carboxamidomethyl-imidazolidine

A mixture of 4.0 g (81.6 mmoles) of sodium cyanide, 80 ml of drydimethylsulfoxide and 3.1 g (8.1 mmoles) of1,3-bis(2',6'-dimethylphenyl)-2-acetimino-4-chloromethyl-imidazolidine,obtained as described in Example 36, is stirred at 100° to 105° C. forone hour. The mixture is cooled, poured onto 200 ml of ice water, andallowed to stand overnight. Next day the separated precipitate isfiltered off, washed with water and dried. 2.8 g (98.6%) of1,3-bis(2',6'-dimethylphenyl)-2-imino-4-carboxamidomethyl-imidazolidineare obtained. This crude product, melting at 90°-96° C., is sufficientlypure to subject it to further reactions. After recrystallization fromisopropanol the product melts at 100°-102° C.

EXAMPLE 38 1,3-Bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-aceticacid

A mixture of 2.2 g (6.3 mmoles) of1,3-bis(2',6'-dimethylphenyl)-2-imino-4-carboxamidomethyl-imidazolidine,obtained as described in Example 37, and 20 ml of concentratedhydrochloric acid is heated on a steam bath for 0.5 hours. The solutionis cooled, washed thrice with 10 ml of chloroform each, and the aqueousphase is evaporated under reduced pressure. The solid residue, weighing1.55 g, is dissolved in 30 ml of acetonitrile, the solution is filtered,and the solvent is evaporated under reduced pressure. The residue iscrystallized by triturating it with diisopropyl ether. 1.2 g (46.9%) of1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-acetic acidhydrochloride monohydrate are obtained, m.p.: 134°-138° C.

When the above product is allowed to stand at room temperature in ethylacetate for 2 days, a transesterification reaction occurs, the ethyl1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-acetate, meltingat 142°-144° C., is obtained.

EXAMPLE 39 (B-Hydroxyethyl)1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-acetatehydrochloride

One proceeds as described in Example 38, with the difference that1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-acetic acidhydrochloride monohydrate, obtained according to Example 79, is appliedas starting substance. (B-Hydroxyethyl)1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-acetatehydrochloride, melting at 106°-109° C., is obtained with a yield of91.0%.

EXAMPLE 401,3-Bis(2',6'-dimethylphenyl)-2-imino-4-acetoxymethyl-imidazolidine

A solution of 5.4 g (16,7 mmoles) of1,3-bis(2',6'-dimethylphenyl)-2-imino-4-hydroxymethyl-imidazolidine,obtained as described in Example 6, in 60 ml of methanol is acidified topH=3 with isopropanolic hydrochloric acid (acid content: about 15 g/100ml), and then the solvents are evaporated under reduced pressure. 6.0 g(100%) of the respective hydrochloride are obtained; m.p.: 219°-220° C.

This salt is dissolved in 40 ml of dry dimethylformamide, 2.45 ml (1.82g, 18 mmoles) of dry triethylamine are added, and 1.30 ml (1.43 g, 18.2mmoles) of acetyl chloride are added dropwise to the mixture at atemperature between 0° C. and +5° C. The reaction mixture is stirred forone hour at this temperature and for an additional hour at a temperaturebetween -20° C. and -15° C., the separated triethylamine hydrochlorideis filtered off, and washed with a small amount of colddimethylformamide. 2.1 g (85.0%) of the salt are obtained. The filtrateis evaporated under reduced pressure, and the oily residue is trituratedwith ethyl acetate. The separated crystalline substance is filtered off,washed with ethyl acetate and dried. 6.1 g (91.0%) of1,3-bis(2',6'-dimethylphenyl)-2-imino-4-acetoxymethyl-imidazolidinehydrochloride are obtained; m.p.: 184°-186° C. After recrystallizationfrom isopropanol the product melts at 187°-188° C.

EXAMPLE 411,3-Bis(2',6'-dimethylphenyl)-2-acetimino-4-bromomethyl-imidazolidine

5.0 g (13.7 mmoles) of1,3-bis(2',6'-dimethylphenyl)-2-acetimino-4-hydroxymethyl-imidazolidine,obtained as described in Example 40, are added in a single portion to astirred solution of 4.45 g (20.5 mmoles) ofbromomethylene-dimethyl-ammonium bromide (see D. R. Hepburn and H. R.Hudson, loc. cit.) in 50 ml of dry acetonitrile at room temperature. Ahomogeneous, yellow solution is being formed within some seconds, andafter about 1 minute a colourless precipitate starts to separate fromthe mixture. The reaction mixture is stirred and boiled for 3 hours andthen allowed to stand overnight. Next day the precipitate is filteredoff, washed with acetonitrile and dried. In this way 6.5 mmoles (47.4%)of the starting substance are recovered as the hydrobromide. Theacetonitrile filtrate is diluted with 100 ml of water, 50 ml ofchloroform are added, and the mixture is rendered alkaline with 2 naqueous sodium hydroxide solution. The aqueous phase is separated andextracted twice with 50 ml of chloroform each. The organic solutions arecombined, washed thrice with 30 ml of water each, dried over anhydrouspotassium carbonate, and the solvent is evaporated. The obtained sticky,solid residue is recrystallized from diisopropyl ether to obtain 1.7 g(29.0%, or, calculated for the converted starting substance, 55.1%) of1,3-bis(2',6'-dimethylphenyl)-2-acetimino-4-bromomethyl-imidazolidine;m.p.: 171°-174° C.

EXAMPLE 421,3-Bis(2',6'-dimethylphenyl)-2-imino-4-bromomethyl-imidazolidine

One proceeds as described in Example 66, with the difference that1,3-bis(2',6'-dimethylphenyl)-2-acetimino-4-bromomethyl-imidazolidine,obtained as described in Example 81, is applied as starting substance,and 1 n aqueous hydrochloric acid is substituted for the 20% aqueoushydrochloric acid.1,3-Bis(2',6'-dimethylphenyl)-2-imino-4-bromomethyl-imidazolidinehydrochloride is obtained with a yield of 91.3%; m.p.: 116°-118° C.(decomposition).

EXAMPLE 43(+)-1,3-Bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidine

A 60° C. solution of 3.0 g (20 mmoles) of d-tartaric acid in 20 ml ofethanol is added in a single portion to a 60° C. solution of 6.15 g (20mmoles) of racemic1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidine, preparedas described in Example 3, in 50 ml of ethanol. The mixture is allowedto stand at room temperature for 2 days. Thereafter the separated bigcrystal grains are filtered off, washed with cold ethanol and dried. 5.8g (63.4%) of the d-tartrate are obtained; m.p.: 186°-189° C., [α]_(D) ²⁰=+3.5° (c=1, in methanol). This salt is recrystallized five times fromethanol to obtain 0.7 g (7.7%) of(30)-1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidine-d-tartrate;[α]_(D) ²⁰ =+6.7° (c=1, methanol). The majority of the product melts at181° -182° C., thereafter it crystallizes again upon continued heating,finally it melts at 223°-225° C.

The salt obtained as described above is dissolved in water, the solutionis rendered alkaline with 10 n aqueous sodium hydroxide solution,thereafter the separated optically pure dextrorotatory base is filteredoff, washed thoroughly with water and dried. The product melts at122°-124° C.; [α]_(D) ²⁰ =+22.4° (c=1, in methanol).

EXAMPLE 44 (+)- and(-)-1,3-Bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidine

A 60° C. solution of 6.1 g (16.22 mmoles) of dibenzoyl-d-tartaric acidin 150 ml of ethyl acetate is added to a 60° C. solution of 10.0 g(32.53 mmoles) of racemic1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidine, obtainedas described in Example 3, in 350 ml of ethyl acetate. The mixture isallowed to stand at room temperature for one week, thereafter theseparated crystals are filtered off, washed with ethyl acetate anddried. 8.5 g (39.3%, calculated for the racemic base) of the cruded-tartrate are obtained; m.p.: 117°-119° C., [α]_(D) ²⁰ =+66.1° (c=1, inmethanol).

This crude substance is dissolved in 100 ml of isopropanol, 500 ml ofethyl acetate are added, and the mixture is allowed to stand at roomtemperature for 2 days. The separated crystals are filtered off, washedwith ethyl acetate and dried. 5.9 g (27.2%) of pure(+)-1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidinedibenzoyl-d-tartrate are obtained; m.p.: 123°-125° C., [α]_(D) ²⁰ +68.4°(c=1, in methanol).

The above pure salt is dissolved in 50 ml of methanol, the solution isrendered alkaline with 2 n aqueous sodium hydroxide solution, 300 ml ofwater are added, and the mixture is allowed to stand at +5° C.overnight. Next day the separated crystals are filtered off, washed withwater and dried. 2.2 g (22.0%) of(+)-1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidine areobtained; m.p.: 118°-121° C., [α]_(D) ²⁰ =+22.2° (c=1, in methanol).

The above pure salt is dissolved in 50 ml of methanol, the solution isrendered alkaline with 2 n aqueous sodium hydroxide solution, 300 ml ofwater are added, and the mixture is allowed to stand at +5° C.overnight. Next day the separated crystals are filtered off, washed withwater and dried. 2.2 g (22.0%) of(+)-1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidine areobtained; m.p.: 118°-121° C., =+22.2° (c=1, in methanol).

The ethyl acetate mother liquor obtained in the salt formation step isevaporated under reduced pressure, the residue is triturated with drydiethyl ether, and the insolubles are filtered off. The etheral filtrateis evaporated under reduced pressure, and the residue is crystallizedfrom cyclohexane. 0.7 g (7.0%) of(-)-1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidine areobtained; m.p.: 119°-122° C., optical purity grade: 81.8%, [α]_(D) ²⁰=-18.3° (c=1, in methanol).

EXAMPLE 451,3-Bis(2',6'-dimethylphenyl)-2-acetimino-4-methylene-imidazolidine

0.5 ml of a 2 n methanolic sodium methoxide solution are added to asolution of 0.43 g (1 mmole) of1,3-bis(2',6'-dimethylphenyl)-2-acetimino-4-bromomethyl-imidazolidine,obtained as described in Example 81, in 10 ml of dry benzene, and theresulting mixture is stirred and boiled for 3 hours. The mixture iscooled, the solvent is evaporated under reduced pressure, and theresidue is triturated with water. The insoluble solid is filtered off,washed with water and dried. 0.31 g (89.5%) of1,3-bis(2',6'-dimethylphenyl)-2-acetimino-4-methylene-imidazolidine areobtained; m.p.: 203°-206° C.

EXAMPLE 46 Copper(I)bromide complex of1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidine (C₂₀ H₂₅N₃.0.75 CuBr)

1.8 g (0.0125 moles) of copper(I)bromide are dissolved in 100 ml of dryacetonitrile under boiling, the insolubles are filtered off, and theresulting clear solution is added dropwise to a stirred and boiledsolution of 3.07 g (0.01 moles) of1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidine, preparedas described in Example 3, in 100 ml of dry ethyl acetate,. The mixtureis stirred and boiled for further 30 minutes, thereafter the resultinggreen solution is fitered and concentrated to a final volume of about 50ml. 200 ml of ethyl acetate are added to the concentrate, and theseparated crystals are filtered off. 1.9 g of the aimed complex areobtained; m.p.: 255°-257° C.

The filtrate is allowed to stand for 2 days, whereupon further 1.55 g ofthe complex separate. Thus a total amount of 3.45 g (77%, calculated forthe organic base) of the complex is obtained.

EXAMPLE 471,3-Bis(2',6'-dimethylphenyl)-2-imino-4-(β-aminoethyl)-imidazolidine

A solution of 2.4 g (0.0068 moles) of1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-acetamide,obtained as described in Example 77, in 30 ml of dry tetrahydrofuran isadded dropwise to a stirred mixture of 10 ml of 1.68 molar boranesolution in tetrahydrofuran and 10 ml of dry tetrahydrofuran at atemperature of 5° to 10° C. The resulting mixture is stirred at roomtemperature for 3 hours and then at the boiling point for 1 hour. Themixture is cooled with ice, 7 ml of 20% aqueous hydrochloric acid areadded dropwise, thereafter the solvent is evaporated under reducedpressure. The residue is dissolved in 30 ml of water, the aqueoussolution is rendered alkaline with 5 n aqueous sodium hydroxidesolution, and the separated crystalline substance is filtered off. 2.0 g(87.0%) of crude(1,3-bis(2',6'-dimethylphenyl)-2-imino-4-(β-aminoethyl)-imidazolidineare obtained. The product melts at 128°-129° C., after recrystallizationfrom diisopropyl ether.

EXAMPLE 48 Tablets

Tablets for oral administration, containing 30 mg of active ingredient,can be prepared e.g. with the following composition:

    ______________________________________                                        1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-                               imidazolidine fumarate hydrate                                                                          45.7 mg                                             lactose                   44.3 mg                                             potato-starch             13.0 mg                                             polyvinyl pyrrolidone     5.0 mg                                              silicium dioxide (colloidal)                                                                            1.0 mg                                              magnesium stearate        1.0 mg                                                                        110.0 mg                                            ______________________________________                                    

EXAMPLE 49 Ointments

Ointments for topical application, containing 0.5% of active ingredient,can be prepared e.g. with the following composition:

    ______________________________________                                        1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-                               imidazolidine fumarate hydrate                                                                          0.76 g                                              distilled water           72.00 g                                             cetostearyl alcohol (BPC 1973)                                                                          12.00 g                                             polysorbate 60 (BPC 1973) 4.00 g                                              paraffin oil              4.00 g                                              vaseline (white)          2.00 g                                              solution of methyl hydroxybenzoate (Ph. Hg. VI)                                                         2.00 g                                              distilled water           ad 100.00 g                                         ______________________________________                                    

What we claim is:
 1. A compound of the formula (I), ##STR7## wherein R¹and R⁵ each represent a phenyl group optionally substituted with 1 to 3carbon lower alkoxy, halo, lower alkyl, monohalo- lower -alkyl, dihalo-lower -alkyl and/or trihalo- lower -alkyl groups,R² stands for hydrogen,formyl, carboxy, lower alkoxycarbonyl, hydroxy-alkoxycarbonyl,unsubstituted lower alkyl, or a lower alkyl group substituted withhydroxy, 1 to 3 halogen atoms, lower alkoxy, lower alkanoyloxy, cyano,an amino group or a group of the general formula --CO--Y, wherein Ystands for hydroxy, amino, lower alkoxy or hydroxy- lower -alkoxy group,R³ and R⁴ each represent hydrogen atoms or a lower alkyl group, with theprovision that when R¹ and R⁵ each represent a phenyl group, R² and R³may not stand for hydrogen; or a pharmaceutically acceptable acidadditon salt, an inorganic meta salt complex, a pure isomer or aisomeric mixture thereof. 2.1,3-bis(2',6'-Dimethylphenyl)-2-imino-4-methyl-imidazolidine and itspharmaceutically acceptable salts.
 3. A compound according to claim 1selected from the group consisting of:(a)1,3-bis(2',6'-dimethylphenyl)-2-imino-4-methyl-imidazolidine fumerate;(b) 1,3-bis(2',6'-dimethylphenyl)-2-imino-4-chloromethyl imidazolidine;(c) 1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-carboxylicacid; (d)1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-acetamide; (e)1,3-bis(4'-chlorophenyl)-2-imino-4-methyl-imidazolidine; (f)1-(4'-chlorophenyl)-2-imino-3-(2',6'-dimethylphenyl)-4-methyl-imidazolidine;andthe pharmaceutically acceptable salts, metal complexes and isomericforms thereof.
 4. A pharmaceutical composition containing anantiphlogistic effective amount of a compound of the formula (I), inclaim 1, or a pharmaceutically acceptable acid addition salt, aninorganic metal salt complex, a pure isomer or an isomeric mixturethereof, together with a pharmaceutical carrier, additive and/orauxiliary agent.
 5. The pharmaceutical composition containing anantiphlogistically effective amount of the compound according to claim 3and a pharmaceutical carrier, additive or an auxiliary agent.
 6. Thepharmaceutical composition containing an antiphlogistically effectiveamount of the compound according to claim 2 and a pharmaceuticalcarrier, additive or an auxiliary agent.